The present invention relates to a process for the preparation of resin-bound xcex1-hydroxyamides and xcex1-ketoamides which is adaptable for the preparation of Combinatorial Chemical Libraries.
Polymer resin-bound substrates have been used for peptide synthesis since R. B. Merrifield first described his methodology for chemical synthesis on a solid matrix. In fact, resin-bound reactions have become ubiquitous toward the application of Combinatorial Libraries.
Isocyanides are reagents which are useful for the preparation of many nitrogen containing cyclic and acyclic compounds. I. Ugi et al., have used these reagents to prepare compounds under multicomponent reaction (MCR) conditions, for example, in the 4 component Ugi Reaction first described in 1959 (I. Ugi et al., Angew. Chem., 1959, 71, 386). However, the simple use of isocyanide as a means for converting aldehydes to xcex1-hydroxyamides and xcex1-ketoamides on a solid phase resin has heretofore not been described.
There is a long felt need for a means for preparing xcex1-hydroxy-amides and xcex1-ketoamides in a manner which is adaptable to solid state synthetic procedures, as well as Combinatorial Libraries.
The present invention meets the aforementioned need in that it has been surprisingly discovered that the isocyanide functional group can be used as a reagent for a carbon-nitrogen two-atom homologation reaction which produces xcex1-hydroxyamides. In addition, this reaction can be extended to accomplish the solid phase preparation of xcex1-ketoamides.
The first aspect of the present invention relates to a process for preparing a xcex1-hydroxyamide, said process comprising the steps of:
a) reacting a resin which comprises a polymer-supported isocyanide having the formula: 
xe2x80x83with an aldehyde having the formula: 
xe2x80x83in the presence of a catalyst, to form a resin-bound xcex1-hydroxyamide having the formula: 
xe2x80x83b) reacting said resin-bound xcex1-hydroxyamide with a reagent which cleaves the nitrogen-resin bond to form a xcex1-hydroxyamide having the formula: 
xe2x80x83wherein J is a compatible organic radical which is not capable of reacting with said resin which comprises a polymer-supported isocyanide in step (a).
The second aspect of the present invention relates to a process for preparing a xcex1-ketoamide, said process comprising the steps of:
a) reacting a resin which comprises a polymer-supported isocyanide having the formula: 
xe2x80x83with an aldehyde having the formula: 
xe2x80x83in the presence of a catalyst, to form a resin-bound xcex1-hydroxyamide having the formula: 
b) oxidizing said resin-bound xcex1-hydroxyamide to a xcex1-ketoamide having the formula: 
c) reacting said resin-bound xcex1-ketoamide with a reagent which cleaves the nitrogen-resin bond to form a xcex1-ketoamide having the formula: 
xe2x80x83wherein J is a compatible organic radical which is not capable of reacting with said resin which comprises a polymer-supported isocyanide in step (a).
These and other objects, features, and advantages will become apparent to those of ordinary skill in the art from a reading of the following detailed description and the appended claims. All percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (xc2x0 C.) unless otherwise specified. All documents cited are in relevant part, incorporated herein by reference.
The present invention relates to a process for preparing xcex1-hydroxyamides and xcex1-ketoamides. The process of the present invention can be adapted to the preparation of any xcex1-hydroxyamides or xcex1-ketoamides, including amino acids and other nitrogen atom containing synthetic intermediates. The process of the present invention is especially useful for introducing a xcex1-hydroxy amido or xcex1-keto amido functionality into molecules having base sensitive protecting groups.
For the purposes of the present invention the term xe2x80x9chydrocarbylxe2x80x9d is defined herein as any organic unit or moiety which is comprised of carbon atoms and hydrogen atoms. Included within the term hydrocarbyl are the heterocycles which are described herein below. Examples of various non-heterocyclic hydrocarbyl units include pentyl, 3-ethyloctanyl, 1,3-dimethylphenyl, cyclohexyl, cis-3-hexyl, 7,7-dimethylbicyclo[2.2.1]heptan-1-yl, and naphth-2-yl.
Included within the definition of xe2x80x9chydrocarbylxe2x80x9d are the aromatic (aryl) and non-aromatic carbocyclic rings, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, bicyclo-[0.1.1]-butanyl, bicyclo-[0.1.2]-pentanyl, bicyclo-[0.1.3]-hexanyl (thujanyl), bicyclo-[0.2.2]-hexanyl, bicyclo-[0.1.4]-heptanyl (caranyl), bicyclo-[2.2.1]-heptanyl (norboranyl), bicyclo-[0.2.4]-octanyl (caryophyllenyl), spiropentanyl, diclyclopentanespiranyl, decalinyl, phenyl, benzyl, naphthyl, indenyl, 2H-indenyl, azulenyl, phenanthryl, anthryl, fluorenyl, acenaphthylenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like.
The term xe2x80x9cheterocyclexe2x80x9d includes both aromatic (heteroaryl) and non-aromatic heterocyclic rings non-limiting examples of which include: pyrrolyl, 2H-pyrrolyl, 3H-pyrrolyl, pyrazolyl, 2H-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isoxazolyl, oxazoyl, 1,2,4-oxadiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-pyran-2-one-yl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, s-triazinyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 1,4-oxazinyl, morpholinyl, azepinyl, oxepinyl, 4H-1,2-diazepinyl, indenyl 2H-indenyl, benzofuranyl, isobenzofuranyl, indolyl, 3H-indolyl, 1H-indolyl, benzoxazolyl, 2H-1-benzopyranyl, quinolinyl, isoquinolinyl, quinazolinyl, 2H-1,4-benzoxazinyl, pyrrolidinyl, pyrrolinyl, quinoxalinyl, pyrrolyl, furanyl, thiophenyl, benzimidazolyl, and the like each of which can be substituted or unsubstituted. A non-limiting example of a C1 heterocycle is tetrazole
The term xe2x80x9csubstitutedxe2x80x9d is used throughout the specification. The term xe2x80x9csubstitutedxe2x80x9d is defined herein as xe2x80x9cencompassing moieties or units which can replace a hydrogen atom, two hydrogen atoms, or three hydrogen atoms of a hydrocarbyl moiety. Also the term xe2x80x9csubstitutedxe2x80x9d can include replacement of hydrogen atoms on two adjacent carbons to form a new moiety or unit.xe2x80x9d For example, a substituted unit that requires a single hydrogen atom replacement includes halogen, hydroxyl, and the like. A two-hydrogen atom replacement includes carbonyl, oximino, and the like. A two-hydrogen atom replacement from adjacent carbon atoms includes epoxy, and the like. Threehydrogen replacement includes cyano, and the like. The term xe2x80x9csubstitutedxe2x80x9d is used throughout the present specification to indicate that a hydrocarbyl moiety, inter alia, aromatic ring, alkyl chain, can have one or more of the hydrogen atoms replaced by a substituent. When a hydrocarbyl unit is described as xe2x80x9csubstitutedxe2x80x9d any number of the hydrogen atoms may be replaced. For example, 4-hydroxyphenyl is a xe2x80x9csubstituted aromatic carbocyclic ringxe2x80x9d, (N,N-dimethyl-5-amino)octanyl is a xe2x80x9csubstituted C8 alkyl unit, 3-guanidinopropyl is a xe2x80x9csubstituted C3 alkyl unit,xe2x80x9d and 2-carboxypyridinyl is a xe2x80x9csubstituted heteroaryl unit.xe2x80x9d There may also be substitutions at more than one carbon atom in a hydrocarbyl moiety, for example, 3,5-difluorobenzene, and 2,3-dihydroxy butane. The following are non-limiting examples of units which can serve as a replacement for hydrogen atoms when a hydrocarbyl unit is described as xe2x80x9csubstituted.xe2x80x9d
i) xe2x80x94[C(R4)2]p(CHxe2x95x90CH)qR4; wherein p is from 0 to 12; q is from 0 to 12;
ii) xe2x80x94C(X)R4;
iii) xe2x80x94C(X)2R4;
iv) xe2x80x94C(X)CHxe2x95x90CH2;
v) xe2x80x94C(X)N(R4)2;
vi) xe2x80x94C(X)NR4N(R4)2;
vii) xe2x80x94CN;
viii) xe2x80x94CNO;
ix) xe2x80x94CF3, xe2x80x94CCl3, xe2x80x94CBr3;
x) xe2x80x94N(R4)2;
xi) xe2x80x94NR4CN;
xii) xe2x80x94NR4C(X)R4;
xiii) xe2x80x94NR4C(X)N(R4)2;
xiv) xe2x80x94NHN(R4)2;
xv) xe2x80x94NHOR4;
xvi) xe2x95x90NOR4;
xvii) xe2x80x94NCS;
xviii) xe2x80x94NO2;
xix) xe2x80x94OR4;
xx) xe2x80x94OCN;
xxi) xe2x80x94OCF3, xe2x80x94OCCl3, xe2x80x94OCBr3;
xxii) xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, xe2x80x94I, and mixtures thereof;
xxiii) xe2x80x94SCN;
xxiv) xe2x80x94SO3M;
xxv) xe2x80x94OSO3M;
xxvi) xe2x80x94SO2N(R4)2;
xxvii) xe2x80x94SO2R4;
xxviii) xe2x80x94P(O)H2;
xxix) xe2x80x94PO2;
xxx) xe2x80x94P(O)(OH)2;
xxxi) and mixtures thereof;
wherein R4 is hydrogen, substituted or unsubstituted C1-C20 linear, branched, or cyclic alkyl, C6-C20 aryl, C7-C20 alkylenearyl, and mixtures thereof; M is hydrogen, or a salt forming cation; X is oxygen, sulfur, xe2x95x90NR4, and mixtures thereof. Suitable salt forming cations include, sodium, lithium, potassium, calcium, magnesium, ammonium, and the like. Non-limiting examples of an alkylenearyl unit include benzyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl.
Formation of xcex1-Hydroxyamides
The process of the present invention, which provides for the synthetic transformation of an aldehyde to a two atom homologated xcex1-hydroxyamide, is depicted in the following general scheme: 
wherein J represents a compatible organic radical. The term xe2x80x9ccompatible organic radicalxe2x80x9d is defined herein as a hydrocarbyl unit which is not capable of reacting with the resin bound isocyanide moiety.
In general, the first aspect of the present invention comprises the steps of:
a) reacting a resin which comprises a polymer-supported isocyanide having the formula: 
xe2x80x83with an aldehyde having the formula: 
xe2x80x83in the presence of a catalyst, to form a resin-bound xcex1-hydroxyamide having the formula: 
xe2x80x83and
b) reacting said resin-bound xcex1-hydroxyamide with a reagent which cleaves the nitrogen-resin bond to form a xcex1-hydroxyamide having the formula: 
Resin Comprising a Polymer-Supported Isocyanide
Step (a) of each aspect of the present invention relates to the reaction of a xe2x80x9cresin comprising polymer-supported isocyanidexe2x80x9d with an aldehyde unit. Any high molecular weight polymer which can be modified to comprise an isocyanide moiety is suitable for use in the present process.
One embodiment is to provide a hydroxyl unit comprising polystyrene resin, inter alia, Merrifield resin, Wang resin and react this resin with a molecule which can be readily converted to an isocyanide, for example, an amino acid which can be converted to an isocyanide by the procedure described herein below. Another embodiment for providing a resin comprising an isocyanide is to chemically modify a resin having an existing amino group, inter alia, a Rink resin.
Step (a)
Step (a) of the present invention comprises the step of reacting an aldehyde with a resin which comprises a polymer-supported isocyanide in the presence of a catalyst to form a resin-bound xcex1-hydroxyamide.
One embodiment relates to catalyst systems which comprise trifluoroacetic acid and an organic base. Non-limiting examples of suitable bases are selected from the group consisting of substituted or unsubstituted pyridine, piperidine, lutidine, s-triazine, and salts thereof.
Step (a) may be conducted in the presence of a solvent, one iteration of which is to utilize a non-polar solvent. Non-limiting examples of suitable solvents are those which are selected from the group consisting of dichloromethane (CH2Cl2), dichloroethane (C2H4Cl2), 1,1,1-trichloro-ethane (CCl3CH3), carbon tetrachloride (CCl4), chloroform (CHCl3), benzene, toluene, xylene, tetrahydrofuran (THF), diethyl ether, and mixtures thereof. One embodiment of the present invention utilizes CH2Cl2 as a solvent for both the reaction performed in step (a), as well as a means for pre-swelling the resin prior to usage.
Step (a) of the present invention can be conducted at any temperature ranging from xe2x88x9278xc2x0 C. to 25xc2x0 C. (ambient temperature). However, different embodiments will require varying the temperature range depending upon reactivity of the aldehyde and isocyanide resin. One iteration of step (a) is conducted at a temperature of from xe2x88x9278xc2x0 C. to 0xc2x0 C., while another iteration is conducted at a temperature of from xe2x88x9215xc2x0 C. to 25xc2x0 C. One embodiment of step (a) includes first combining the reactants at a temperature of xe2x88x9215xc2x0 C. and allowing the reactants to warm to 0xc2x0 C. over time. This embodiment can be extended to allow the reactants to warm to ambient temperature (25xc2x0 C.).
Step (a) can be conducted under an inert atmosphere when desirable. Any source of inert gas, inter alia, dry nitrogen or argon is suitable for use in conducting step (a).
The first aspect of the present invention relates to the formation of xcex1-hydroxyamides, however, both the first and second aspects of the present invention have step (a) in common. The only differences which may arise between the first and second aspects of the present invention may relate to the degree to which the product of step (a) is isolated. The second step of the second aspect is the oxidation of the hydroxyamide to the ketoamide and the chosen means for this oxidation may require a more rigorous isolation than would be required if only the cleavage reaction remained.
One embodiment of the first aspect of the present invention relates to the formation of a xcex1-hydroxyamide which comprises a nitrogen-containing functionality other than the amide nitrogen which is introduced into the molecule via step (a). One iteration relates to xcex1-hydroxyamides have the formula: 
wherein R is a unit having the formula: 
each R1, R2, and R3 are independently hydrogen, C1-C20 substituted or unsubstituted hydrocarbyl, C1-C20 substituted or unsubstituted heterocyclic, and mixtures thereof; R1 and R2 can be taken together to form a single C1-C20 substituted or unsubstituted hydrocarbyl or C1-C20 substituted or unsubstituted heterocyclic unit; the index x is from 1 to 20.
Another iteration of this aspect relates to the use of the present process as part of an overall scheme to convert an amino acid to the corresponding xcex1-hydroxyamide or xcex1-ketoamide. As it relates to this iteration (xcex1-amino acids) one R3 is hydrogen and while the other R3 unit is selected from the group consisting of hydrogen (glycine), methyl (alanine), 1-methylethyl (valine), 2-methylpropyl (leucine), 1-methylpropyl (isoleucine), amidomethyl (asparagine), 2-amidoethyl (glutamine), 2-mercaptoethyl (cysteine), 2-methythioethyl (methionine), 3-guanidinopropyl (arginine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 3-aminopropyl (ornithine), 4-aminobutyl (lysine), hydroxymethyl (serine), 1-hydroxyethyl (threonine), (4-imidazolyl)methyl (histidine), (3-indolyl)methyl (tryptophan), benzyl (phenylalanine), and 4-hydroxybenzyl (tyrosine). For this iteration the index x is equal to one.
This iteration of the first aspect typically requires protection of the amino group nitrogen with a protecting group that is not acid labile. One embodiment is to utilize nitrogen protecting such carbobenzyloxy, 9-fluorenylmethoxycarbonyl, 9-(2-sulfo)fluorenyl-methoxycarbonyl, or benzyl. Another embodiment utilizes protecting groups such as phthalimido wherein R1 and R2 are taken together to form a C8 aryl hydrocarbyl unit, for example, a starting material aldehyde having the formula: 
wherein R3 is an amino acid side chain.
Another iteration of the present invention relates to conducting step (a) under phase transfer conditions. For example, step (a) can be modified to comprise:
a) suspending a resin which comprises a polymer-supported isocyanide in a non-polar solvent comprising a catalyst to form a non-aqueous phase, dissolving an amino aldehyde in water comprising a phase transfer catalyst to form an aqueous phase, and contacting said non-aqueous phase with said aqueous phase to form a resin-bound xcex1-hydroxyamide.
Step (b)
Step (b) of the first aspect of the present invention comprises the step of reacting a resin-bound xcex1-hydroxyamide formed in step (a) with a reagent which is effective in cleaving the nitrogen-resin chemical bond thereby releasing a xcex1-hydroxyamide.
In one iteration of step (b) the nitrogen-resin is cleaved by a system comprising:
i) from 15% to 95% by volume, of trifluoroacetic acid; and
ii) a carbocation scavenger.
Depending upon the embodiment, the formulator will adjust the amount of trifluoroacetic acid which is necessary to complete the fragmentation reaction. The carbocation scavenger can be any reagent which will quench the carbocation which is formed during the course of the reaction of step (b). Non-limiting examples of a scavenger is selected from the group consisting of dimethyl silane, triisopropylsilane, and mixtures thereof.
Step (b) may be conducted in the presence of a solvent, one iteration of which is to utilize a non-polar solvent. Non-limiting examples of suitable solvents are those which are selected from the group consisting of dichloromethane (CH2Cl2), dichloroethane (C2H4Cl2), 1,1,1-trichloro-ethane (CCl3CH3), carbon tetrachloride (CCl4), chloroform (CHCl3), benzene, toluene, xylene, tetrahydrofuran (THF), diethyl ether and mixtures thereof. One embodiment of the present invention utilizes CH2Cl2 as a solvent.
The second aspect of the present invention relates to the inclusion of the optional step of oxidizing the xcex1-hydroxyamide which is formed in step (a) having the formula: 
with an oxidizing agent to form a xcex1-ketoamide having the formula: 
prior to cleavage from the resin. The oxidation can be conducted with any suitable oxidizing agent, including by way of enzymatic oxidation. Non-limiting examples of oxidizing agent are selected from the group consisting of (1,1,1-triacetoxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin reagent), pyridine sulfoxide, 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO), sodium hypochlorite, pyridinium dichromate, pyridinium chlorochromate, DMSO/oxalyl chloride (Swern oxidation), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), and mixtures thereof.
As it relates to the second aspect of the present invention, the formation of the resin-bound xcex1-hydroxyamide and cleavage reaction are the same.